Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GH deficiency (GHD) is associated with increased prevalence of atherosclerosis and cardiovascular morbidity. Because monocytes play a crucial role in the development of atherosclerosis, we investigated in the present study the effect of GH deficiency and subsequent GH replacement on monocytic function in hypopituitary subjects. Twelve patients were randomized to receive GH replacement therapy (either 3 or 6 microg/kg x day, s.c.) for 3 months. Plasma levels and monocyte production of cytokines and monocyte adhesion to endothelium were determined in controls and patients with GHD before and after GH treatment. Before GH therapy, patients with GHD had increased basal plasma tumor necrosis factor-alpha (TNF alpha; 220% over control values; P = 0.004) and interleukin-6 (IL-6; 340% over control values; P 0.0009) levels. Basal monocyte production of both cytokines was also significantly higher in patients with GHD [484% over control values for TNF alpha (P = 0.0007); 1479% over control values for IL-6 (P = 0.035)]. GH treatment for 3 months led to a reduction in plasma TNF alpha (135% over control values; P = 0.03, pre- vs. post-GH therapy), monocyte TNF alpha production (204% over control values; P = 0.01), plasma IL-6 (219% over control values; P = 0.07), and monocyte IL-6 production (448% over control values; P = 0.01). Plasma TNF alpha levels positively correlated with monocyte TNF alpha production in patients with GHD both before and after GH therapy (P = 0.003 and P = 0.049, respectively). A positive correlation (P = 0.0003) was also observed between monocyte TNF alpha production and monocyte IL-6 production. There were no correlations between these plasma cytokine levels or monocyte cytokine production and parameters of body composition, lipid profile, or IGF-I and IGF-binding protein-3 levels. Before GH treatment, adhesiveness of monocytes to cultured aortic endothelial cells was also enhanced. This alteration was not reversed by GH administration. In conclusion, our results demonstrate that markers of monocyte activation are increased in patients with GHD and that GH replacement partly reduces these abnormalities. Reduction of cellular activation of monocytes by GH therapy could potentially contribute to reduce the risk of cardiovascular events in patients with GHD.
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PMID:Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy. 1048 24

The acute phase response induces a multitude of changes in lipoprotein metabolism including hypertriglyceridemia, triglyceride enriched LDL, and decreased HDL levels accompanied by changes in HDL composition including increased free cholesterol and triglycerides and a decrease in esterified cholesterol. Here we demonstrate that endotoxin (LPS) induces a 56% decrease in hepatic lipase activity in liver and a 45% decrease in hepatic lipase activity in post heparin plasma in Syrian hamsters. LPS treatment also produces a marked decrease in hepatic lipase mRNA levels in the liver. Half maximal reduction in hepatic lipase mRNA levels occurred at approximately 0.2 microg LPS/100 g BW with a maximal decrease at 1.0 microg/100 g BW ( > 90% decrease), indicating that inhibition of hepatic lipase is a sensitive host response to LPS. Additionally, IL-1 produced a marked decrease in hepatic lipase mRNA levels while TNF had no effect. Moreover, IL-1 treatment of HepG2 cells in vitro also decreased hepatic lipase mRNA levels suggesting that IL-1 can directly regulate hepatic lipase expression in liver cells. LPS decreased hepatic lipase mRNA levels in control as well as IL-1 type 1 receptor deficient mice indicating that IL-1 action is not absolutely essential and that several cytokines and/or small molecular mediators can regulate hepatic lipase during the acute phase response. The LPS and IL-1 induced decrease in hepatic lipase could have several consequences including decreasing the clearance of triglyceride rich lipoprotein particles and producing an increase in triglyceride rich HDL. The decrease in hepatic lipase activity and mRNA levels may be part of a series of coordinated changes in lipoprotein metabolism that occur during the acute phase response. These changes may be initially beneficial to the host but if present for an extended period may be proatherogenic.
Atherosclerosis 1999 Feb
PMID:Endotoxin and interleukin-1 decrease hepatic lipase mRNA levels. 1003 Mar 89

In the diabetic vascular complication, biochemical and mechanical injuries to endothelial cells are involved not only in the process of microangiopathy, but also in diabetic atherosclerosis (or arteriosclerosis) which is so-called macroangiopathy. In the presence of diabetes or persistent hyperglycemia, many cytokines including growth factors such as PDGF, HB-EGF, IL-1 beta and TNF alpha are upregulated in intimal cells of the arterial or aortic wall. These changes alter the cytokine network in the common mechanism of atherosclerosis, "Response-to-injury hypothesis", and further accelerate the formation of atherosclerotic lesion. In addition, diabetes causes abnormal responsibility to HB-EGF, PDGF and TGF-beta in medial smooth muscle cells leading to the elevated activity to their proliferation and migration into the intima. Thus, all cell types consisting arterial or aortic wall are involved in the process of diabetic atherosclerosis.
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PMID:[Mechanism of atherosclerosis in diabetes: altered cytokine network in the vascular wall]. 1019 40

Omega-3 fatty acids (n-3 FA) may reduce atherogenesis and thrombosis. We investigated the effects of n-3 FAs on procoagulant activity and cytokine expression in whole blood cultures from patients with atherosclerosis. Eleven of the 23 included patients had received 5.1 g n-3 FA daily for 6 months (group I) whereas 12 patients had been on placebo (group II). All patients were then given 5. g n-3 FA daily for another 4 weeks. At baseline significantly lower levels of LPS-induced prothrombin fragment1+2 were found in group I (p = 0.010), this difference being eliminated after 4 weeks. Il-6 and TNFalpha were significantly higher at baseline in group I and the differences in changes from baseline between the groups were statistically highly significant with increasing values in group II(Il-6 p = 0.001, TNF alpha p = 0.002). The present results indicate a reduction in pro-thrombotic potential in patients receiving highly concentrated n-3 FA, whereas some proinflammatory responses might be adverse.
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PMID:Procoagulant activity and cytokine expression in whole blood cultures from patients with atherosclerosis supplemented with omega-3 fatty acids. 1023 40

Obesity is associated with a cluster of abnormalities, including hypertension, insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor beta (TGF-beta). Although these changes may increase the risk for accelerated atherosclerosis and fatal myocardial infarction, the underlying molecular mechanisms remain to be defined. Although tumor necrosis factor alpha (TNF-alpha) has been implicated in the insulin resistance associated with obesity, its role in other disorders of obesity is largely unknown. In this report, we show that in obese (ob/ob) mice, neutralization of TNF-alpha or deletion of both TNF receptors (TNFRs) results in significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and adipose tissue PAI-1 and TGF-beta mRNAs. Studies in which exogenous TNF-alpha was infused into lean mice lacking individual TNFRs indicate that TNF-alpha signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the p75 TNFR. However, TNF-alpha signaling of TGF-beta mRNA expression in adipose tissue is mediated exclusively via the p55 TNFR. Our results suggest that TNF-alpha is a common link between the insulin resistance and elevated PAI-1 and TGF-beta in obesity. The chronic elevation of TNF-alpha in obesity thus may directly promote the development of the complex cardiovascular risk profile associated with this condition.
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PMID:Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. 1035 11

Human vascular smooth muscle cells (VSMC) are a component of blood vessels, and secrete a variety of cytokines in atherosclerotic loci. Interleukin-11 (IL-11), a member of IL-6-like cytokines, is reported to be involved in inflammation and tissue remodeling, both of which are observed in atherosclerosis. However, no information is available as to the production of IL-11 by VSMC. Therefore, the expression of IL-11 in VSMC is investigated. The amounts of IL-11 protein and mRNA were determined by enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis, respectively. The expression of IL-11 in VSMC was also immunohistochemically determined. IL-1 alpha, transforming growth factor-beta (TGF beta) and, to a lesser extent, tumor necrosis factor-alpha (TNF alpha) stimulated the IL-11 production by VSMC, and the stimulatory effects of IL-1 alpha and TGF beta on IL-11 production were dose-dependent. IL-1 alpha and TNF alpha synergistically augmented TGF beta-stimulated IL-11 production by VSMC. Immunohistochemical staining also revealed the expression of IL-11 protein in VSMC. Furthermore, IL-1 alpha, TGF beta, and TNF alpha induced IL-11 gene expression in VSMC. Because IL-6-like cytokines are reported to be cytoprotective, monokine-stimulated IL-11 may have a potent protective role in atherosclerotic lesions.
Atherosclerosis 1999 Jun
PMID:Monokine stimulation of interleukin-11 production by human vascular smooth muscle cells in vitro. 1040 98

Inflammatory phenomena at sites of atherosclerotic plaques are increasingly thought to be major determinants of the progression and clinical outcome of atherosclerotic disease. Therefore, attention is being paid to systemic markers/mediators which may reflect the inflammatory activity in the plaques. This study evaluates the pattern of the main proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), their soluble receptors/antagonist, and a variety of inflammatory markers, in patients with peripheral arterial disease (PAD). Eight patients with PAD suffering from claudicatio intermittens (CI), eight with critical limb ischemia (CLI) and eight controls (C) were studied. Blood samples were collected at baseline in all groups and. for C and CI, immediately after and 4 h after a 30-min treadmill test. Baseline: no differences in cytokine plasma levels were detected among the three groups. In contrast, soluble receptors of TNF (type I and II) and of IL-6, and IL-1beta receptor antagonist (IL-1ra) were increased in CI and CLI patients, as compared to C. Of note, IL-Ira correlated with the occurrence and stage of the disease in a highly significant proportion of the patients, reaching a predictive value for the disease of P < 0.0001. The opposite trend was observed for the soluble receptor of IL-1beta. Notably, in the patients no alterations could be found in white blood cell counts, expression of CD11c adherence molecule by circulating monocytes or, in vitro. O2- release from zymosan-activated neutrophils. Moreover, plasma levels of platelet activating factor (PAF), of neutrophil elastase and of the acute phase reactants C-reactive protein (CRP) and alpha1-acid glycoprotein were not found to be significantly altered. In contrast, the acute-phase proteins alpha1-antitrypsin (alpha1AT) and haptoglobin (HG) were found to be increased. Effect of treadmill: IL-1beta and TNFalpha remained at baseline levels following exercise, and IL-6 dropped to undetectable levels. Among cytokine antagonists, again the most relevant changes concerned the IL-1ra, which was significantly increased immediately after the treadmill test, both in CI and C, and returned to baseline levels after 4 h. In contrast, soluble TNFalpha, IL-1beta and IL-6 receptors, PAF, and the other markers of leukocyte activation were not found to be altered. Soluble TNFalpha and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase proteins alpha1AT and HG have been reported to exert anti-inflammatory functions. The increased plasma levels of these agents, together with low levels of inflammatory cytokines and other pro-inflammatory mediators such as PAF and alpha1-acid glycoprotein, appear to draw an undescribed picture, so far, of upregulation of a composite systemic anti-inflammatory mechanism in atherosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for developing new insights into the pathogenesis of the atherosclerotic disease.
Atherosclerosis 1999 Jul
PMID:Atherosclerosis and inflammation. Patterns of cytokine regulation in patients with peripheral arterial disease. 1042 95

Little is known about the requirements and function of zinc in maintaining endothelial cell integrity, especially during stressful conditions, such as the inflammatory response in cardiovascular disease. There is evidence that zinc requirements of the vascular endothelium are increased during inflammatory conditions such as atherosclerosis, where apoptotic cell death is also prevalent. Apoptosis is a morphologically distinct mechanism of programmed cell death which involves the activation of a cell-intrinsic suicide program, and there is evidence that factors such as inflammatory cytokines (e.g., tumor necrosis factor [TNF]) and pure or oxidized lipids are necessary to induce the cell death pathway. Because of its constant exposure to blood components, including prooxidants, diet-derived fats, and their derivatives, the endothelium is very susceptible to oxidative stress and to apoptotic injury mediated by blood lipid components, prooxidants, and cytokines. Thus, it is likely that the cellular lipid environment, primarily polyunsaturated fatty acids, can potentiate the overall endothelial cell injury by increasing cellular oxidative stress and cytokine release in proximity to the endothelium, which then could further induce apoptosis and disrupt endothelial barrier function. Our data suggest that zinc deficiency exacerbates the detrimental effects of specific fatty acids (e.g., linoleic acid) and inflammatory cytokines, such as TNF, on vascular endothelial functions. We propose that a major mechanism of zinc protection against disruption of endothelial cell integrity during inflammatory conditions, is by the ability of zinc to inhibit the pathways of signal transduction leading to apoptosis and especially mechanisms that lead to upregulation of caspase genes.
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PMID:Zinc nutrition and apoptosis of vascular endothelial cells: implications in atherosclerosis. 1050 Dec 86

Accumulating evidence suggest that infection with Chlamydia pneumoniae is associated with atherosclerosis, but the mechanisms involved remain unclear. Inflammation is important in the initial phase of atherogenesis, and cytokines are important in the initiation and progression of inflammation. The aim of this study was to assess the capacity of acellular components of C. pneumoniae to stimulate the production of pro-inflammatory cytokines and chemokines. Peripheral blood mononuclear cells were stimulated in vitro with sonicated C. pneumoniae. Significant amounts of TNF-alpha, IL-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) were produced. Inhibition of endotoxin using polymyxin B revealed that chlamydial endotoxin plays a minor role in the cytokine induction. Neutralization of TNF by TNF-binding protein and blockade of IL-1 receptors by IL-1 receptor antagonist revealed that TNF, IL-1 and IL-6 production was independent from each other, whereas IL-8 synthesis was strongly dependent on endogenous TNF and IL-1. In contrast, synthesis of MCP-1 and MIP-1alpha was dependent on endogenous TNF, but not IL-1. In conclusion, acellular components of C. pneumoniae are a potent stimulus for cytokine production, and this mechanism may have an important role in the inflammatory aspects of atherogenesis.
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PMID:Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells. 1067 Dec 10

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71


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